Surprising Clue to Parkinson's

When George Carillo arrived at the Santa Clara Valley Medical Center in San Jose one steamy July day in 1982, he seemed more a mannequin than a man. The 42-year-old heroin addict was bent over and twisted, drooling and unable to speak; almost every muscle was immobilized. No one knew what to make of his condition, so a call went out for Dr. J. William Langston, the hospital's chief neurologist. Langston took one look and was amazed. Carillo's symptoms suggested that he had been suffering for at least a decade from Parkinson's disease, a nervous system disorder that causes tremors and a gradual loss of mobility. But that hardly seemed plausible: Parkinson's rarely strikes anyone under the age of 50.

Using stiffened fingers to scrawl answers to doctors' questions, Carillo managed to provide a few clues. The symptoms had come on suddenly after he and his girlfriend, Juanita Lopez, 3l, had tried a new synthetic heroin. Though the drug had caused an odd burning sensation when injected and hallucinations, they continued to use it for three days; two days later both had frozen into living statues.

With help from colleagues at Stanford University, where he teaches, Langston located Lopez and had her hospitalized. A tip from a neurologist in Watsonville, 30 miles away, led him to two more cases: a pair of brothers, both addicts in their 20s, with advanced Parkinson's symptoms. By now Langston was alarmed. He called a press conference to announce that bad heroin was on the streets; he urged that anyone suffering from stiffness and tremors come forward. The appeal uncovered three more cases.

The seven cases in Santa Clara County attracted the attention of local drugenforcement officials and Parkinson's researchers at the National Institute of Mental Health (NIMH), who joined the hunt to identify the deadly ingredient in samples of the drug obtained by police. Their task was made easier by an alert toxicologist at the county crime laboratory, who recalled the 1977 case of a Maryland graduate student who had developed Parkinson's symptoms after injecting himself with a home-brewed opiate. The student had been trying to produce MPPP, a substance similar to the pain-killer Demerol, but had accidentally created a related chemical called MPTP. Langston asked Stanford University Chemist Ian Irwin to test the samples for the drug. Sure enough, MPTP was there.

While public health authorities worried about additional cases of drug- induced Parkinson's and police pondered how to stop the sale of a drug that was not illegal (see box), medical researchers could hardly contain their excitement. The tragic outbreak in California could hold the key to understanding and treating Parkinson's disease, which afflicts some 350,000 Americans.

The scientists quickly turned to the task. For years research on Parkinson's disease has been limited by the lack of an animal model on which to test new drugs and treatments. Would MPTP induce Parkinson's in animals? The answer, NIMH Researchers Sanford Markey and R. Stanley Burns soon discovered, was no in rats but yes in monkeys. Says Markey: "That was probably the biggest breakthrough in this story."

The next step was to find out how MPTP did its damage. Doctors have known since the 1930s that Parkinson's occurs as a result of the deterioration of a small, darkly pigmented region of the brain called the substantia nigra. This region produces most of the brain's supply of dopamine, a vital chemical in the transmission of nerve signals. Normally, people lose 5% to 8% of the cells in this region each decade of their lives and suffer no serious consequences. But for reasons that are unclear, the loss is more rapid in the case of Parkinson's victims; once approximately 80% of these cells are gone, the symptoms appear. The usual treatment is a drug called L-dopa, which is converted into dopamine in the brain, but the efficacy of the drug may decline after years of use.

MPTP's role soon became clear. Researchers learned that once the chemical enters the bloodstream, it is converted into another molecule (called MPP+) that appears to attack the substantia nigra like a guided missile, causing the kind of damage found in all Parkinson's victims. Later experiments showed that if the conversion of MPTP to MPP+ was blocked with chemical inhibitors, a laboratory animal would not develop Parkinsonian symptoms even if given large doses of MPTP. Would human victims also respond to such treatment? At least one drug that blocks MPTP metabolism, Deprenyl, is already used in Europe to treat Parkinson's disease in its final stages. Langston suspects that if used much earlier, "Deprenyl might actually retard the progress of the disease." He has applied for FDA permission to test his theory on Parkinson's victims.

The MPTP cases have led some scientists to suspect that most Parkinson's disease is caused by exposure to toxic substances similar to MPTP. Researchers are looking for culprit chemicals in one rural area of Canada, where the incidence of Parkinson's runs five times higher than in other areas, and on the island of Guam, where, until 1965, one out of five deaths was due to a form of Parkinson's. The United Parkinson Foundation in Chicago meanwhile has mailed questionnaires to 36,000 Parkinson's sufferers around the country, asking them to name every town in which they have ever lived, their drinking- water sources and industries located within a 25-sq.-mi. radius of their homes. Explains Executive Director Judy Rosner: "We want to get a handle on environmental influences."

California public health officials are facing the more immediate problem of what to do about MPTP exposure among addicts. Langston and a team of investigators from the Centers for Disease Control in Atlanta have determined that more than 300 people in the state have used the drug and that it is still being sold on the street. The CDC is now working with state authorities to stem the tide of MPTP and stop it from spreading beyond California.

But no one knows what will become of those already exposed. Of 150 MPTP users examined by CDC researchers, as many as half had subtle signs of Parkinson's. Says Langston: "There may be a large number of people out there with half the nerve cells they're supposed to have." In ten or 15 years, he predicts, as these addicts continue to lose substantia nigra cells as part of the normal aging process, California may become the scene of a Parkinson's epidemic.